Abstract 12677: The Nitric Oxide Redox Sibling Nitroxyl Partially Circumvents Platelet Nitric Oxide Resistance in Patients With Ischaemic Heart Disease
Introduction: Impaired platelet responsiveness to nitric oxide (NO resistance) is a common characteristic of many cardiovascular diseases and represents an independent risk factor for cardiac events and mortality. NO resistance reflects both NO scavenging by superoxide (O2-), and impairment of NO receptor, heme-containing soluble guanylate cyclase (sGC). There is thus an urgent need for circumvention of NO resistance in order to improve clinical outcomes. Hypothesis: We tested the hypothesis that nitroxyl (HNO), a reduced form of NO that shares sGC activation but is not inactivated by O2-, circumvents NO resistance in human platelets.
Methods: In 51 patients with or without ischemic heart disease, aged 66±17 years, platelet responsiveness to HNO donor isopropylamine NONOate (IPA; 10μ M) and NO donor sodium nitroprusside (SNP; 10μ M) were compared in whole blood, utilizing inhibition of ADP (2.5μ M)-induced aggregation. IPA effects were also assessed in presence of NO scavenger carboxy-PTIO (CPTIO; 50μ M) and sGC oxidizing agent ODQ (10μ M).
Results: The relationship between platelet responsiveness to SNP and to IPA was best described by a hyperbolic function (Figure). In NO-resistant patients (defined as SNP response <35%; n=32), the IPA:SNP response ratio was markedly increased (p<0.01) but IPA responses were also reduced (p<0.001), consistent with partial circumvention of NO resistance. IPA-induced inhibition of platelet aggregation was suppressed by 37±8% by ODQ (p<0.005), and by 9±2% by CPTIO (p<0.01). On multivariate analysis, clinical patient characteristics did not identify poor responders to IPA.
Conclusions: (1) IPA anti-aggregatory effects are largely NO and partially heme-independent. (2) Although effects of IPA are attenuated in NO-resistant patients, there is still partial circumvention of NO resistance, which may translate to clinical utility of HNO-releasing agents in acute management of cardiovascular disease states.
- © 2012 by American Heart Association, Inc.